Most of the common causes of liver injury result in cirrhosis. Cirrhosis is the destruction of normal liver tissue that leaves non-functioning scar tissue surrounding areas of functioning liver tissue, accompanied with the formation of regenerative liver nodules. In the United States, the most common cause of cirrhosis is alcohol abuse. Among people ages 45 to 65, cirrhosis is the third most common cause of death, after heart disease and cancer. In many parts of Asia and Africa, chronic hepatitis is a major cause of cirrhosis. Many people with mild cirrhosis have no symptoms and appear to be well for years. Others are weak, have a poor appetite, feel sick, and lose weight. If bile flow is chronically obstructed, the person has jaundice, itching, and small yellow skin nodules, especially around the eyelids. Malnutrition commonly results from a poor appetite and the impaired absorption of fats and fat-soluble vitamins caused by the reduced production of bile salts. Occasionally, the person may cough up or vomit large amounts of blood because of bleeding from varicose veins at the lower end of the esophagus (esophageal varices). These enlarged blood vessels result from high blood pressure in the veins that run from the intestine to the liver. Such high blood pressure, called portal hypertension, along with poor liver function, may also lead to fluid accumulation in the abdomen (ascites). Kidney failure and liver encephalopathy also may develop. Other symptoms of long-standing liver disease may develop, such as muscle wasting, redness of the palms (palmar erythema), a curling up of the fingers (Dupuytren's contracture of the palms), small spider-like veins in the skin, breast enlargement in men (gynecomastia), salivary gland enlargement in the cheeks, hair loss, shrinking of the testes (testicular atrophy), and abnormal nerve function, both in the periphery (peripheral neuropathy) and in the central nervous system.
At present, no cure exists for cirrhosis. Treatment includes withdrawing toxic agents such as alcohol, receiving or providing proper nutrition including supplemental vitamins, and treating complications as they arise. Liver transplantation is presently the only cure, and may help a person with advanced cirrhosis. Moreover, the presence of cirrhosis increases the risk of developing hepatocellular carcinoma to about 40-fold over the risk in the general population and, in an etiological background of chronic hepatitis and alcoholism, the development of cirrhosis multiplies the already increased risk to the patient of developing hepatocellular carcinoma from 34.4 to 119-fold and from 2.4 to 22.4-fold, respectively (Kuper et al., 2001). Usually, a number of blood tests are performed to measure liver function and to help determine the severity and cause of cirrhosis. One of the most important factors indicative of liver damage is bilirubin, a red-yellow pigment that is normally metabolized in the liver and then excreted in the urine. In patients with hepatitis, the liver cannot process bilirubin, and blood levels of this substance rise, sometimes causing jaundice.
The levels of certain liver enzymes can also be indicative for cirrhosis (e.g., aspartate and alanine aminotransferase levels and several clotting enzymes). However, results of these liver function tests often are normal because only a small percentage of functioning liver cells are needed to carry out essential chemical functions. In addition, a number of imaging tests are used to diagnose possible cirrhosis and its complications. For example, an ultrasound scan may show that the liver is enlarged and that particular lesions, such as regenerative nodules, are present. Other, much more costly, imaging techniques are magnetic resonance imaging (MRI) and computed tomography (CT). In most of the patients presenting with some form of chronic liver disorder, liver biopsy is performed to assess the degree of fibrosis and to detect the presence of cirrhosis (Fracanzani et al., 2001). As liver biopsy is an invasive procedure, it is generally difficult to perform it on a regular follow-up basis in the normal clinical setting. A specific serum marker for the detection of liver cirrhosis could thus have a very significant impact on gastroenterology practice, in allowing regular follow-up of chronic liver disease patients, and in providing early warning for the onset of cirrhosis. In the particular case of chronic alcoholism, a serum marker for cirrhosis could provide an important argument to convince the patient to stop drinking.
Measurement of diagnostic glycans in carbohydrate metabolism diseases is described in the art (PCT International Publication No. WO9219975). In the field of hepatic disorders, it is also known that single glycosylation enzyme activities are altered in liver disorders. For example an increased activity of the enzyme UDP-N-acetyl-glucosamine:glycoprotein N-acetyl-glucosaminyl-transferase (GnTIII) is correlated with the progression of liver disease (Ishibashi et al., 1989), a finding that has recently been elaborated upon in a diagnostic setting (Mori et al., 1998). However, these assays are complicated by the HPLC separation of the products of the enzymatic reaction. Moreover, the stability of the enzyme in serum in storage conditions is unknown and the values obtained for serum GnTIII activity have large overlaps between cirrhosis and chronic hepatitis. Glycosylation differences have also been studied on a purified protein, serum transferrin, and these differences are used for the detection of chronic alcoholism (Matsumoto K. et al., 1994, Clin. Chim. Acta 224(1): 1-8). Alterations in the carbohydrate moiety of single purified proteins have also been described in human cirrhotic ascitic fluid (Biou, D. et al., 1987, Biochimica et Biophysica Acta 913, 308-312). Methods for the detection of liver diseases are described in patents EP0503886 and DE3838718. However, the latter patents deal with the quantification of simple carbohydrates (fucose) in urine.
There is currently no easily measurable, reliable serum marker for the differentiation of liver cirrhosis from other hepatic disorders.